Animal feed and process

ABSTRACT

A process for increasing production in meat-producing, egg-laying or milk-producing animals comprising feeding a compound of the formula: ##STR1## wherein R is a member selected from the group consisting of hydrogen, R 5 , ##STR2## wherein R 5  is alkyl of from 1 to 8 carbon atoms, inclusive, including isomeric forms thereof, alkenyl of from 2 to 8 carbon atoms, inclusive, including isomerici forms thereof, cycloalkyl of from 3 to 7 carabon atoms; or lower acyl wherein acyl is up to and including 5 carbon atoms; R 1  is a member selected from the group consisting of R 5  and ##STR3## wherein R 6  is selected from the group consisting of hydrogen, ##STR4## or acyl wherein acyl is up to and including 5 carbon atoms; R 2  is a member selected from the group consisting of hydrogen, R 5 , bromo of chloro; R 3  and R 4  are the same or different and are selected from the group consisting of hydrogen, provided that R 3  and R 4  are not both hydrogen, R 5 , cycloalkyl of from 3 to 8 carbon atoms, alkyl substituted cycloalkyl of the formula ##STR5## wherein n is an integer of from 2 to 7, inclusive and R 7  is a member selected from the group consisting of hydrogen and alkyl of from 1 to 5 carbon atoms, inclusive, including isomeric forms thereof; alkenyl of from 2 to 8 carbon atoms, inclusive, including isomeric forms thereof, aralkyl wherein Ar is a member selected from the group consisting of phenyl, substituted phenyl wherein 1 or 2 hydrogens are replaced with chlorine, fluorine, bromine, iodine, R 5 , --OR 5 , or --CF 3  and the substituents can be the same or different, and alkyl is from 1 to 4 carbon atoms, inclusive, including isomeric forms thereof, and R 3  and R 4  taken together with --N&lt; is a heterocyclic moiety of from 4 to 8, inclusive, ring atoms and 1 or 2 hetero atoms selected from the group consisting of nitrogen, oxygen or sulfur or a substituted heterocyclic moiety wherein 0, 1, 2 or 3 of the carbon atoms of the heterocycle are substituted with R 5  in combination with a nutrient animal feed.

DESCRIPTION Brief Summary of the Invention

Broadly the present invention encompasses a nutritionally adequateanimal feed having dispersed therein a compound of the Formula Ia and Ibin sufficient concentration to provide increasing productivity and feedefficiencies in healthy meat-producing, milk-producing or egg-layinganimals. The invention also includes the process of administering thecomposition to meat-producing, milk-producing, egg-laying orwool-producing animals.

BACKGROUND OF THE INVENTION

It has been found in recent years that meat-producing animals will gainmore weight and gain it faster when various classes of compounds such asvitamins, minerals, estrogens, antibiotics, and tranquilizers are addedto the diet. Although the presently available compounds are useful, newmaterials are still being sought that would produce weight gains morerapidly, to a greater extent, more efficiently with respect to feedintake at a lower cost and without undesirable side effects.

DETAILED DESCRIPTION OF THE INVENTION

It is now possible by use of the present invention to obtain unexpectedresults in the feeding of meat-producing, milk-producing, or egg-layinganimals; that is to say, an increased rate of weight gain, an increasedamount of weight gain, an increase in milk production enhanced woolproduction, or increased rate of egg laying, as well as increased feedefficiency, can be obtained by the addition of minute quantities of acompound of the Formula I to the animals usual nutrient feed.

The active compounds pyridine oxides are represented by the structure I:##STR6## wherein R is a member selected from the group consisting ofhydrogen, R₅, ##STR7## wherein R₅ is alkyl of from 1 to 8 carbon atoms,inclusive, including isomeric forms thereof, alkenyl of from 2 to 8carbon atoms, inclusive, including isomeric forms thereof, cycloalkyl offrom 3 to 7 carbon atoms; or lower acyl wherein acyl is up to andincluding 5 carbon atoms; R₁ is a member selected from the groupconsisting of R₅ and ##STR8## wherein R₆ is selected from the groupconsisting of hydrogen, ##STR9## or lower acyl wherein acyl is up to andincluding 5 carbon atoms; R₂ is a member selected from the groupconsisting of hydrogen, R₅, bromo or chloro; R₃ and R₄ are the same ordifferent and are selected from the group consisting of hydrogen,provided that R₃ and R₄ are not both hydrogen, R₅, cycloalkyl of from 3to 8 carbon atoms, alkyl substituted cycloalkyl of th formula ##STR10##wherein n is an integer of from 2 to 7, inclusive, and R₇ is a memberselected from the group consisting of hydrogen and alkyl of from 1 to 5carbon atoms, inclusive, including isomeric forms thereof; alkenyl offrom 2 to 8 carbon atoms, inclusive, including isomeric forms thereof,aralkyl wherein Ar is a member selected from the group consisting ofphenyl, substituted phenyl wherein 1 or 2 hydrogens are replaced withchlorine, fluorine, bromine, iodine, R₅, --OR₅ or --CF₃ and thesubstituents can be the same or different, and alkyl is from 1 to 4carbon atoms, inclusive, including isomeric forms thereof, and R₃ and R₄taken together with --N is a heterocyclic moiety of from 4 to 8,inclusive, ring atoms and 1 or 2 hetero atoms selected from the groupconsisting of nitrogen, oxygen or sulfur or a substituted heterocyclicmoiety wherein 0, 1, 2 or 3 of the carbon atoms of the heterocycle aresubstituted with R₅.

Compounds of the Formula I can be prepared by methods disclosed in U.SPat. No. 4,021,562.

The pyridine oxides of Formula I are amines, and exist in thenon-protonated or free base form, or in the protonated or acid additionsalt form, depending on the pH of the environment. They form stableprotonates, i.e., mono- or diacid addition salts, on treatment withsuitable acids, for example, hydrochloric, hydrobromic, sulfuric,phosphoric, nitric, acetic, benzoic, salicylic, glycolic, succinic,nicotinic, tartaric, maleic, malic, pamoic, methanesulfonic,cyclohexanesulfamic, picric, and lactic acids, and the like.

Examples of alkyl are methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, and isomeric forms thereof. Examples of alkenyl areallyl, 1-methylallyl, 2-methylallyl (methallyl), 2-butenyl (crotyl),3-butenyl, 1,2-dimethylallyl, 1,1-dimethylallyl, 2-ethylallyl,1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 3-pentenyl,2,3-dimethyl-2-butenyl, 1,1,2-trimethylallyl, 1,3-dimethyl-2-butenyl,1-ethyl-2-butenyl, 4-methyl-2-pentenyl, 2-ethyl-2-pentenyl,4,4-dimethyl-2-pentenyl, 2-heptenyl, 2-octenyl, 5-octenyl,1,4-dimethyl-4-hexenyl, and the like. Examples of cycloalkyl arecyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl,2,3-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl,2-methylcyclobutyl, 3-propylcyclobutyl, 2,3,4-triethylcyclobutyl,cyclopentyl, 2,2-dimethylcyclopentyl, 3-pentylcyclopentyl,3-tert-butylcyclopentyl, cyclohexyl, 4-tert-butylcyclohexyl,3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl, cycloheptyl, cyclooctyl,and the like. Examples of aralkyl are benzyl, phenethyl, 1-phenylethyl,2-phenylpropyl, 4-phenylbutyl, 5-phenyl-2-methylpentyl,1-naphthylmethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl, and thelike. Examples of acyl are acetyl, propionyl, butanoyl, pentanoyl, andthe like. Examples of alkoxycarbonyl are carbomethoxy, carboethoxy, andthe like. Examples of heterocyclic moieties of the present invention arepiperidino, pyrrolidinyl, morpholino, 2,4,4-trimethylazetidinyl,2,3,4-trimethylazetidinyl, 2-methylpyrrolidinyl, 3-butylpyrrolidinyl,2-isohexylpyrrolidinyl, 2,3-dimethylpyrrolidinyl,2,2-dimethylpyrrolidinyl, 2,5-diethylpyrrolidinyl,3-tert-butylpyrrolidinyl, 2,3,5-trimethylpyrrolidinyl,3,4-dioctylpyrrolidinyl, 2-methylpiperidino, 3-methylpiperidino,4-methylpiperidino, 3-isopropylpiperidino, 4-tert-butylpiperidino,2-methyl-5-ethylpiperidino, 3,5-dipentylpiperidino,2,4,6-trimethylpiperidino, 2,6-dimethylpiperidino,2,6-dimethyl-4-octylpiperidino, 2,3,5-triethylpiperidino,2-ethylhexahydroazepinyl, 4-tert-butylhexahydroazepinyl,3-heptylhexahydroazepinyl, 2,4-dimethylhexahydroazepinyl,3,3-dimethylhexahydroazepinyl, 2,4,6-tripropylhexa-hydroazepinyl,2-methylheptamethylenimino, 5-butylheptamethylenimino,2,4-diisopropylheptamethylenimino, 3,3-diethylheptamethylenimino,2,5,8-trimethylheptamethylenimino, 3-methyloctamethylenimino,2,9-diethyloctamethylenimino, 4-isooctyloctamethylenimino,2-ethylmorpholino, 2-methyl-5-ethylmorpholino, 3,3-dimethylmorpholino,2,6-di-tert-butylmorpholino, 4-methylpiperazinyl,4-isopropylpiperazinyl, 2-methylaziridinyl, 2-ethylaziridinyl,2-butylaziridinyl, 2,3-dimethylaziridinyl, 2,2-dimethylaziridinyl,2-methylazetidinyl, 3-methylazetidinyl, 2-octylazetidinyl,2,2-dimethylazetidinyl, 3,3-diethylazetidinyl, and the like.

Unless otherwise specified, all percentages are given on aweight-to-weight basis. The pound (lb) weights given are avoirdupoisunits.

Administration of the compositions of the present invention can commencefor birds shortly after hatching and in the case of mammals, during thecreep-feeding period of suckling animals when they are starting on solidfood and, of course, after weaning. Feeding of the compositions iscontinued throughout the growing period, lactation period, or egg-layingperiod. In addition to feeding the active ingredient in combination withthe feed, the active compounds can alternatively be administered incombination with the animals drinking water or in combination with apharmaceutical carrier by injection or implantation.

The total concentration of the compound of the Formula in the feedcomposition is determined with regard to the species of animal, sex,age, weight, and average amount of feed consumed daily. Preferably thecompound of the Formula I is employed in the finished feed that willsupply the animal with a daily intake of from about 0.02 mg to about 200mg per head, per day.

The following table illustrates the range of compound of Formula inmilligrams daily dose, per head, per day for representative animals.

    ______________________________________                                                     Range          Preferred                                         Animal       Daily Dose/Head, mg                                                                          Daily Dose, mg                                    ______________________________________                                        Swine (birth to                                                                            0.5-20.0       10.0                                              8 weeks)                                                                      Swine (40 to 200                                                                           1.0-140.0      50.0                                              lbs)                                                                          Chickens (growing                                                                          0.02-2.0       0.05                                              0-8 weeks)                                                                    Hens (laying)                                                                              0.1-2.0        1.0                                               Turkeys (growing                                                                           0.1-5.0        2.0                                               0-24 weeks)                                                                   Beef Cattle  0.5-50.0       10                                                (fattening)                                                                   Calves       1.0-40.0       10                                                (0-12 weeks)                                                                  Dairy Cattle 5.0-200.0      10                                                (lactation)                                                                   Lambs        1.0-20.0       10                                                (fattening)                                                                   ______________________________________                                    

The foregoing dosages can generally be accomplished by providing fromabout 50 mg to about 20,000 mg of a compound of the Formula per ton offinished feed.

Advantageously a compound of the Formula is supplied in the form of aliquid or solid premix wherein the concentration is 100-2,000 timesgreater than the desired final concentration in the feed. For example,the compound of Formula can be dissolved or suspended in a fluid vehiclesuch as corn oil, cottonseed oil, molasses, distillers solubles and thelike to prepare a fluid premix. Alternatively, a solid premix can beprepared by mixing a compound of the Formula with an edible soliddiluent such as sucrose, lactose, starch, corn meal, flour, calciumcarbonate, soybean meal and the like.

EXAMPLE 1

A diet for fattening lambs is prepared from the following types andamounts of ingredients:

    ______________________________________                                        Ground ear corn         82.05%                                                Alfalfa meal            10.0%                                                 Soybean oil meal 44%    7.0%                                                  Ground limestone        0.3%                                                  Salt                    0.3%                                                  Trace mineral mixture.sup.1                                                                           0.05%                                                 ______________________________________                                         .sup.1 Contains the following percent of minerals: Mn, 12; Co, 0.08; Fe,      5.0; Cu, 0.4; I, 0.24; Zn, 0.7.                                          

The above feed to be mixed, pelleted and offered to fattening lambsfree-choice in conjunction with hay.

To 999 parts of the preceding feed is added 1 part of a premixcomposition prepared by mixing 7 gm of2,6-diamino-3-piperidinopyridine-1-oxide with sufficient corn meal tomake one pound.

The feeding composition so prepared supplies 7.0 mg of2,6-diamino-3-piperidino-pyridine-1-oxide per pound or 15.4 parts permillion.

The foregoing composition is usefully fed to lambs for increased rate ofweight gain and improved utilization of feed.

EXAMPLE 2

A chicken feed for broilers is prepared from the following types andamounts of ingredients:

    ______________________________________                                        Yellow corn meal        67.35%                                                Soybean oil meal        24.00%                                                Menhaden fish meal      6.00%                                                 Steamed bone meal       1.00%                                                 Ground limestone        1.00%                                                 Iodized salt            .34%                                                  25% Choline chloride    .13%                                                  Vitamin B.sub.12 supplement                                                   (6 mg/lb)               .10%                                                  Manganese sulfate       .02%                                                  Supplemental vitamin mix.sup.1                                                                        .06%                                                  ______________________________________                                         .sup.1 Consisting of 16.0 gm Vitamin A supplement (10 units/mg); 3.6 gm       Vitamin D.sub.3 supplement (15,000) units/gm); 7.1 gm riboflavin              supplement (1 gm riboflavin per ounce); 500 mg niacin.                   

999 parts of the preceding feed is added one part of a premixcomposition prepared by mixing 0.08 gm of2,6-diamino-3-piperidinopyridine-1-oxide with sufficient soybean millfeed to make one pound.

The feeding composition so prepared supplies 0.08 mg of2,6-diamino-3-piperidinopyridine-1-oxide per pound, or about 0.18 partsper million.

The foregoing composition is usefully fed to chickens for increased rateof weight gain and improved utilization of feed. Similarly thecomposition can be fed to turkeys, ducks and geese.

EXAMPLE 3

A fattening feed of 800 pound yearling cattle is prepared from thefollowing types and amounts of ingredients:

    ______________________________________                                        Ground ear corn         89.75%                                                Soybean oil mean, 44%   9.0%                                                  Ground limestone        0.7%                                                  Salt                    0.5%                                                  Trace mineral mixture.sup.1                                                                           0.05%                                                 ______________________________________                                         .sup.1 Contains the following percent of minerals: Mn, 12, Co, 0.08; Fe,      5.0; Cu, 0.4; I, 0.24; Zn, 0.7.                                          

To 999 parts of the preceding feed is added one part of a premixcomposition prepared by mixing 0.5 gm of2,6-diamino-3-piperidinopyridine-1-oxide with sufficient wheat flour tomake one pound.

The feeding composition so prepared supplies 0.5 mg of2,6-diamino-3-piperidinopyridine-1-oxide per pound, or about 11.0 partsper million.

Cattle are to receive the foregoing feed ad libitum together with 5 lbs.of hay, per head, per day and when so fed have an increased rate ofweight gain and improved utilization of feed.

EXAMPLE 4

A swine diet for growing hogs of 40 to 100 pounds body weight isprepared from the following types and amounts of ingredients:

    ______________________________________                                        Corn, ground             78.15%                                               Soybean oil mean, 44%    17.0%                                                Meat and bone scraps, 50%                                                                              3.0%                                                 Oyster shell flour       0.4%                                                 Bone meal                0.5%                                                 Salt                     0.5%                                                 Trace mineral mixture.sup.1                                                                            0.05%                                                Zinc oxide               0.01%                                                Vitamin A and D Supplement.sup.2                                                                       0.25%                                                Vitamin Supplement.sup.3 0.25%                                                Vitamin B.sub.12 supplement.sup.4                                                                      0.09%                                                ______________________________________                                         .sup.1 Contains the following % of minerals: Mn, 12; Co, 0.08; Fe, 5.0;       Cu, 0.4; I, 0.24; Zn, 0.7.                                                    .sup.2 Contains 300 USP units D.sub.2 /Gm. and 1500 I.U. of A./Gm.            .sup.3 Contains per lb.: Riboflavin, 2000 mg.; calcium pantothenate, 4000     mg.; niacin, 9000 mg.; and choline chloride 10,000 mg.                        .sup.4 Contains 6 mg. Vitamin B.sub.12 per lb.                           

To 999 parts of the preceding feed is added one part of a premixcomposition prepared by mixing 10 mg of2,6-diamino-3-piperidinopyridine-1-oxide with sufficient groundlimestone to make one pound.

The feeding composition so prepared supplies 10 mg of2,6-diamino-3-piperidinopyridine-1-oxide per pound or about 22 parts permillion.

The foregoing composition is usefully fed to hogs for increased rate ofweight gain and improved utilization of feed.

EXAMPLE 5

A regimen of 2,6-diamino-3-piperidinopyridine-1-oxide in water isprepared simply by adding the compound to the drinking water asspecified below. The animals are allowed to ingest the water on an adlibitum basis

    ______________________________________                                                                 mg/l                                                 ______________________________________                                        Swine          Birth to 8 weeks                                                                              2.5                                            Swine          40-200 lb       7.0                                            Chickens       0-8 weeks       0.3                                            Hens                           5.0                                            Turkeys        0-24 weeks      3.2                                            Beef cattle                    0.2                                            Calves         0-12 weeks      1.0                                            Dairy cattle                   0.9                                            Lambs                          5.0                                            ______________________________________                                    

EXAMPLE 6

Following the procedure of the preceding Examples 1 to 5, inclusive,animal feeds are similarly prepared substituting equimolar amounts of:

2,6-diamino-4-pyrrolidinopyridine-1-oxide,

2,6-diamino-4-diethylaminopyridine-1-oxide,

2,6-diamino-4-(2-methylpiperidinopyrimidine-1-oxide,

2-amino-6-methyl-4-pyrrolidinopyrimidine 1-oxide,

2-amino-6-methyl-4-piperidinopyrimidine 1-oxide, or

2,6-diamino-4-dialkylaminopyrimidine 1-oxide, for the2,4-diamino-6-piperidinopyrimidine-1-oxide of the example.

An added advantage was observed in the feeding of sheep. The sheepproduced an increased amount of wool. This increase in wool productionwas attributable to the increase in body size (and weight).

We claim:
 1. A process for obtaining increased production inmeat-producing, egg-laying or milk-producing animals comprising feedingto said animals an effective amount of a compound of the formula##STR11## wherein R is a member selected from the group consisting ofhydrogen, R₅, ##STR12## wherein R₅ is alkyl of from 1 to 8 carbon atoms,inclusive, including isomeric forms thereof alkenyl of from 2 to 8carbon atoms, inclusive, and isomeric forms thereof, cycloalkyl of from3 to 7 carbon atoms; or lower acyl wherein acyl is up to and including 5carbon atoms; R₁ is a member selected from the group consisting of R₅and ##STR13## wherein R₆ is selected from the group consisting ofhydrogen, ##STR14## or acyl wherein acyl is up to and including 5 carbonatoms; R₂ is a member selected from the group consisting of hydrogen,R₅, bromo or chloro; R₃ and R₄ are the same or different and areselected from the group consisting of hydrogen, provided that R₃ and R₄are not both hydrogen; R₅, cycloalkyl of from 3 to 8 carbon atoms, alkylsubstituted cycloalkyl of the formula ##STR15## wherein n is an integerof from 2 to 7, inclusive and R₇ is a member selected from the groupconsisting of hydrogen and alkyl of from 1 to 5 carbon atoms, inclusive,including isomeric forms thereof; alkenyl of from 2 to 8 carbon atoms,inclusive, including isomeric forms thereof, aralkyl wherein Ar is amember selected from the group consisting of phenyl, substituted phenylwherein 1 or 2 hydrogens are replaced with chlorine, fluorine, bromine,iodine, R₅, --OR₅ or --CF₃ and the substituents can be the same ordifferent, and alkyl is from 1 to 4 carbon atoms, inclusive, includingisomeric forms thereof; and R₃ and R₄ taken together with --N> is aheterocyclic moiety of from 4 to 8, inclusive, ring atoms and 1 or 2hetero atoms selected from the group consisting of nitrogen, oxygen orsulfur or a substituted heterocyclic moiety wherein 0, 1, 2 or 3 of thecarbon atoms of the heterocycle are substituted with R₅ in combinationwith a nutrient feed.
 2. The process of claim 1 where the memberselected is fed in combination of from 0.001 mg to 10 mg per kilogrambody weight of the animal per day.
 3. The process of claim 1 where themember selected is 2,4-diamino-6-piperidinopyrimidine-3-oxide or an acidaddition salt thereof.
 4. The process of claim 1 wherein the animal is ameat-producing animal.
 5. The process of claim 1 wherein the animal isan egg-laying animal.
 6. The process of claim 1 wherein the animal is amilk-producing animal.
 7. The process of claim 1 wherein the compound ofthe Formula I is hydrogen; R₂ is hydrogen; R₁ is amino, and R₃ and R₄are ethyl or propyl or taken together with --N> is a heterocyclic moietyof from 5 to 7 ring atoms or a substituted heterocyclic moiety whereinone or two of the carbon atoms are substituted with methyl.
 8. Theprocess of claim 1 wherein the compound of the Formula I is hydrogen; R₂is hydrogen; R₁ is alkyl of from 1 to 8 carbon atoms, and R₃ and R₄ areethyl or propyl or taken together with --N> is a heterocyclic moiety offrom 5 to 7 ring atoms or a substituted heterocyclic moiety wherein oneor two of the carbon atoms are substituted with methyl.